Nu-(1-carboxyacylaminoethylthiomethyl) derivatives, and the process of producing them



Patented Nov. 3, 1942 UNITED STATES PATENT OFFICE N (1cannoxmcnamnonrmrmo- METHYL) DERIVATIVES,

ANn run PROCESS or raonucmc THEM Morris s. Kharasch and om Reinmuth, cm-

cago, 11]., assignors to Eli, Lilly and Company,

Indianapolis, Ind., a corporation of Indiana No Drawing. ApplicationJune 3, 1940,

Serial No. 338,657

13 Claims.

amines, to their salts, and to the methods of producing them.

Our new products have been found to be gene eraliy of the'sametherapeutic effectiveness or physiological activity as the parent aminesfrom which they are derived, and to be in general of markedly lowertoxicity than the parent compounds. It is the markedly greater specificdetoxifying effect of the 'l-carboxy-l-acylaminoethylthiomethyl groupthat distinguishes these new products from the other thiomethylderivatives of physiologically active amines described in ourco-pendingapplication, Serial No. 338,656, flied June3, 1940, and in ourco-pending application Serial No. 305,926, filed November 24, 1939 onwhich United States Patent 2,224,156 was granted on December 10, 1940.In general the detoxifying eifect of a l-carboxy-l-acylaminoethylthiomethyl group is from three to five times that of any of theother thiomethyl groups described in our co-pending applications. Inaddition to the relatively low toxicity common to all our newderivatives, many of them are further useful in that their chemical andphysical properties are more desirable in one or more respects thanthose of the parent compounds from which they are derived.

These new derivatives are substituted monoamines which are derived fromthe class consisting of physiologically active primary and secondaryamines and in which a hydrogen atom of the amino group is replaced by. aradial which is represented by the f ollowing formula:

NH- R in which R represents a member of the class of acyl groupsconsisting of those derived from the alkanoic and haloalkanoic acids ofnot more than eight carbon atoms, those derived from the arcmatic andheterocyclic carboxylic acids and those derived from the aromaticsulfonic acids; and X represents a member of the class of positive ionsconsisting of hydrogen, the alkali metals, the normal equivalents of thealkaline earth metals, the nitrogen hydro-onium ions derived fromammonia, the alkylamines, the alkanolamines, and

the polymethylene diamines.

By the term mono-amine, we mean an amino compound in which there is onlyone amino or substituted amino group; but this term monoamine does notexclude the presence in addition to the aminogroup of an amido group orgroups in which an NHz group or substituted NH: group is attacheddirectly to an acyl group.

The mono-amines of our invention are represented by the followingformula:

ncmscm- 0 NH-r-R' uit-- s or- NH:

from sulfanilamide;

from 'sulfapyridine; I

S-CH

. N from sulfathiazole;

from methyl suliathiazole;

from phenyl sulfathiazole;

- from sulfanilhydroxamide;

from sulfanilethanolamide;

from sulfanilylanilide; and

from sulfanilyl-p-nitroanilidel;

in which R and K have the same meaning as.

zene, and acetone.

those derived from the p-aminobenzoic esters. fe. g.,

and those of other physiologically active primary and secondary aminesderived for example from 4-aminoazobenzene, 4-amino-4'-methylazobenzene,4-amino-4-nitroazobenzene, histamine, tyramine, aminoantipyrine,proflavine, ephedasoomc in solution.

.not our usual practice to isolate the. solid acid,

rine alkaloid (a-hydroxy-fi-methylaminopropylbenzene),p-indolylethylamine, and epinephrine. The salts are all freely solublein water, and in general relatively stable in the solid state. The

in absolute alcohol, and insoluble in ether, ben- The ammonium andaminium salts are in general moderately soluble in absolute alcohol, butinsoluble in ether, benzene, and acetone. The acids differ as to theirsolubility in water, and in general are less stable than are the salts.

The sodium salts are, in general, the most conveniently prepared, themost satisfactory in physical properties, and the most useful thera=peutically. Of all of the N-acylcysteine derivatives investigated, weprefer the N-acetylcysteine.

In preparing our new products we proceed in general as follows:

To a solution or suspension of a physiologically active, primary orsecondary amine having the general formula:

in which R has the same significance as heretofore noted, in a suitablesolvent, such as methyl alcohol, ethyl alcohoLethyleine glycol,propylene glycol, ordioxane, we add one molecular equivalent of anaqueous solution of formaldehyde, and one molecular equivalent of anN-acylcysteine of the general formula:

in which R has the same meaning as heretofore noted.

g It is desirable but not necessary to add the aldehyde before addingthe N-acylcysteine. The N-acylcysteine may be added, and it is desirableto add it in moderate excess. The further addition of a relatively smallamount of a strong,

non-oxidizing acid, such as hydrochloric, sulfuric or phosphoric acids,(when the amine is not used in the form of an acid salt), though notimperative, facilitates and greatly expedites the reaction. The totalconcentration of the acid catalyst need not exceed 0.05%.

The formaldehyde and a primary monoamine may be combined to produce anintermediate product; and this intermediate product, separated as suchif desired, although that is 'ordinarily not done, may be treated withthe N-acylcysteine, at a later time and at a different place and in anentirely separate reaction if that is more convenient. But this givesthe same final product.

The ingredients thus brought together react to produce an acid of thetype shown in Formula although the acids'may be isolated if desired.-

If isolation of the acid is desired, some may be precipitated fromsolution by the addition of a relatively large volume of water. This-precipitation may be facilitated by the addition of sodium chloride orother salting-out reagent. The, solid acid thus obtained maybe'separated from thesupernatani; liquid in a suitable manher, as byfiltration, decantation, or centrifugation. As thus obtained, it is anamorphous mass.

This'amorphous mass is washed with water and then dried as in a vacuumdesiccator. To obtain the more water-soluble acids in solid form, we

remove the solvent by evaporation, preferably at low temperature underreduced pressure. The

metallic salts are in general very slightly soluble usually syrupy orgummy acid so obtained is suitably dried, as in a vacuum desiccator.

Salts may be readily obtained from the solutions of the acid prepared asdescribed, by addi- ,alkanolamine, or polymethylenediamine.

' tion of a solution in the same, or .a mutually miscible, anhydroussolvent of the desired base, such as sodium hydroxide or ethoxide,calcium ethoxide, magnesium ethcxide, or by direct addition of ammoniaor with the desired alkylor In general the metallic salts so formedprecipitate by reason of their relative insolubility' in the solventused. If precipitation does not occur, or is incomplete, it may beproducedor brought to completion by adding dry ether or acetone.

In general the ammonium and aminium salts are relativelyalcohol-soluble, but may be obtained in solid form by evaporation of thesolvent and any excess of the base present, preferably at lowtemperature under reduced pressure. In

some cases the salts may also be precipitated from solution by theaddition of dry ether or ethyl alcohol, we add 4.5 cc. of formalin (36%formaldehyde), 5.5 g. of 'N-acetylcysteine (or the 1?: COIH 5)l;ICHr-SCH:CH

NHCOCHr i' f H V The acid represented in Formula 5 may be 100 cc. ofabsolute ethyl alcohol. The sodiumf salt, being relatively insoluble inalcohol. precipitates and is collected by filtration, and dried in avacuum desiccator.

This salt is represented by the formula:

I COzNa (6) N,cH,s-cmc mi-co-cm Example 2. To 7.7 g. of2-(p-aminobenzenesulfonamido)-4-methylthiazole (i. e., methylsulfathiazole) dissolved and suspended in absolute fonvlhydroxamidedissolved and suspended in 100 cc. of absolute alcohol. we add 4.5 cc.offormalin f (36% formaldehyde); 5.5 g. of N-acetylcysteine and 10 dropsof 36% hydrochloric acid and pro- 6 ceed in the manner described inExample 1 to produce the acid or the sodium salt of the acid. The sodiumsalt thus produced is represented by the following formula:

'0: III-OH Example 5.-To 6.5 g. of p-aminobeuzenesul fonylethanolamidedissolved and suspended in 100 cc. of absolute ethyl alcohol, we add 4.5cc. of formalin (36% formaldehyde), 5.5 g. of N-acetylcysteine and 10drops of 36% hydrochloric acid and proceed in the manner described inExample 1 to produce the acid or the sodium salt of the acid. The sodiumsalt thus produced is represented by the following formula:

ethyl alcohol, we add 4.5 cc. of formalin (36% formaldehyde), 5.5 cc.ofN-acetylcysteine and no) f 10 drops of 36% hydrochloric acid. Themixture N-cH,--scmc is shaken at room temperature until the solid I NHCO CH' material is completely dissolved, and water dilution andneutralization with sodium bicarbonate of a'small test portion producesno precipitate of free amine.

The sodium salt is prepared in the same manner as described inExample 1. The sodium salt OH is represented by the following formula:40 I Example 6.To 7.7 g. of 2-(p-aminobenzene- (1) I sulfonylamido)thiazole (i. e., sulfathiazole) dis= NH-c o cn,' solved and suspended in100 cc. of absolute ethyl i= alcohol, we add 4.5 cc. of: formalin (36%formaldehyde), and 8.4 g. of N-p-bromopmpionylcysteine (or equivalent ascalculated upon the 7 basis of the percentage iodine reduction of theso, i l-fi I actual sample used) and 7 drops of a solu- -c C-CH; 50 tionof phosphoric acid; We proceed in the man-. I N ner described in Example1 to produce the acid Example 3.-To 5.2 g.of-p-aminobenzenesulfonylamide (i. e., sulfanilamide) dissolved and orthe sodium salt of the acid. The sodium salt thus produced isrepresented by the following formula:

suspended in 100 cc. of absolute alcohol or other suitable solvent, suchas dioxane, we add 4.5 cc. of formalin (36% formaldehyde), 5.5 g. of N-acetylcysteine and 10 drops of 36% hydrochloric acid and proceed in themanner desc ibed in Example 1 to produce the acid or the sodium salt ofthe acid. The sodium salt thus produced is represented by the followingformula:

H coma Nn-cocm- 0mm cc. of absolute ethyl alcohol, we add 4.5 cc. of

formalin (36% formaldehyde) and 7.5 g. of N- benzocylcysteine (orequivalent as calcul ated upon the basisfiof the percentage iodinereduction of the actual sample used). andlO drops of 36% Example 4.To5.6 g. of p-aminobenzenesulhydrochloric acid. We proceed in the mannerdescribed in Example 1 to produce the acid or the sodium salt of theacid. The acid thus produced is represented by the following formula:

III c0111 N-CHs-S-CEs-CH NH-CO can 1 to produce the acid ,or the sodiumsalt of the Example 8.-To 6.3 g. of 4-arnino-4'-nr1ethyl-- azobenzenedissolved and suspended in 100 cc. of absolute ethyl alcohol, we add 4.5cc. of formalin (36% formaldehyde) and 7.5 g. of N-benzoylcysteine (orequivalent as calculated upon the basis of thepercentage iodinereduction of the actual sample used) and 10 drops of 36% hydrochloricacid. We proceed in the manner described in Example 1 to produce theacid or the sodium salt of the acid. The sodium salt thus produced isrepresented by the following formula:

Example 9.To 4.1 g. of p-phenetidine dissolved and suspended in 100 cc.of absolute ethyl alcohol, we add 4.5 cc. of formalin (36% formaldehyde)and 8.6 g. of N-benzenesulfonylcysteine (or equivalent as calculatedupon the basis of the percentage iodine reduction of the actual sampleused) and 10 drops of 36% hydrochloric acid. We proceed in the mannerdescribed in Example 1 to produce the acid or the sodium salt of theacid. The sodium salt thus produced is represented by the followingformula:

Example 10.To 5.0 g. of ephedrine alkaloid (i. e.,a-hydroxy-fl-methylaminopropylbenzene) dissolved and suspendedin 100 cc.of absolute ethyl alcohol, we add 4.5 cc. of formalin (36% formaldehyde)and 5.5 g. N.-acetylcysteine (or equivalent as calculated upon the basisof the percentage iodine reduction of the actual sample used) and 10drops of 36% hydrochloric acid. We proceed in the manner described inExample acid. The sodium salt thus produced is represented by thefollowing formula:

. COsNa (16) at. cmscm- 0 mc- -11 n-c o-cm Example 11.To 5.2 g. ofuteramlne (i. e., tyramine hydrochloride) dissolved and suspended in cc.of absolute ethyl alcohol, we add 4.5 cc. of formalin (36% formaldehyde)and 5.5 g. of N-acetylcysteine (or equivalent as calculated upon thebasis of the percentage iodine reduction of the actual sample used). Inthis case, no strong non-oxidizing mineral acid is employed as acatalyst since the acid salt of the mono-amine is employed. With thatexception,

the procedure is the same as that described in Example 1 for theproduction of the acid and the sodium salt of the acid. The sodium saltof the acid is represented by the following formula:

Example. 12.To 0.92 g. of histamine phosphate dissolved and suspended in10 cc. of absolute ethyl alcohol, we add 0.45 cc. of formalin (36%formaldehyde) and 0.55 g. N-acetylcysteine (or equivalent as calculatedupon the basis of the percentage iodine reduction of the actual sampleused). In this case, no strong non-oxidizing mineral acid is employed asa catalyst since the acid salt of the mono-amine is employed. With thatexception, the procedure is the sameas that described in Example I forthe production of the acid and the sodium salt of the acid. The sodiumsalt of the acid is represented by the following formula:

Example 13.-To 6.1 g. of aminoantipyrine dissolved and suspended in 100cc. of absolute ethyl alcohol, we add 4.5 cc. of formalin (36%formaldehyde) and 5.5 g. N-acetylcysteine (or equivalent as calculatedupon the basis of the percentage iodine reductionof the actual sample2,300,076 used) and 10 drops of 36% hydrochloric *acid.

We proceed in the manner described in Example- 1 to produce the acid orthe sodium salt of the acid. The sodium salt thus produced is repre-Example 14.-To 8.2 g. novocaine (i. e., procaine hydrochloride)dissolved and suspended in 100 cc. of absolute ethyl alcohol, we add 4.5cc. of formalin (36% formaldehyde) and 5.5 g. N-acetylcysteine (orequivalent as calculated upon the basis of the percentage iodinereduction of the actual sample used) and 10 drops of 5 We prepare theethylenediamine salt containing one molecule of diamine to two moleculesof acid byadding one-half molecular equivalent of diamine to a. solutionof the desired acid derivative prepared as described in Examples 1 to14,

and then proceeding as described above. These diamine salts have ingeneral the most satisfac tory physical properties of all the amine'salts.

In Examples 1 to 9, inclusive, and 14, the structures as indicated inFormulas 5 to 14, inclusive,

and 19 show the physiologically active amine without any methylol groupin the benzene 36% hydrochloric acid. We proceed in the manner describedin Example 1 to produce the acid or the sodium salt of the acid. Thesodium salt thus produced is represented by the following formula:

Example 15.We prepare the calcium and magnesium salts of thederivativesdescribed by adding the appropriate quantities of calcium ethoxide ormagnesium ethoxide, respectively, dissolved in absolute ethyl alcohol tothe alcoholic solutions of the respective acids prepared as described inExamples 1 to 14, inclusive. The salts, which precipitate by reason oftheir relative insolubility in alcohol, are collected by filtration, anddried in a vacuum desiccator. When precipitation is incomplete it isbrought to completion by addition to the solution of a relative y largevolume of dry acetone or ether, preferably the former.

Example 16.We prepare the ammonium salts of the derivatives described bydissolving an excess of dry ammonia gas in the alcoholic solu tionsprepared as described in Examples '1 to 14, inclusive, with simultaneouscooling. The ammonium salts are obtained in solid form by evaporation ofthe solvent (and excess ammonia) at low temperature under reducedpressure, and

by further drying of the amorphous, hygroscopic products so obtained ina vacuum desiccator.

We prepare the ethanolamine, diethanolamine, propanolamine, andisopropanolamine salts, and the ethylenediamine salt containing onemolecule of diamine to one molecule of acid by adding slightly more thanone molecular equivalent of .the desired amine to the alcoholicsolutions of the acid derivatives prepared as described in Examples 1 to14, inclusive. In some cases the salts so formed may be precipitatedfrom alcoholic solution by. the addition of a relatively large volume ofdry acetone or ether, preferably the former. Better yields are obtained,however, by proceeding as described for the ammonium salts above.

nucleus. It is known that when an aromatic primary amine is treated withformaldehyde in acid solution some of the formaldehyde tends to condensewith' the aromatic ring to yield a methylol derivative. It is thereforepossible that the products resulting from the practice of the methodsdescribed in Examples 1 to 9, inclusive, and 14 contain some of themethylol groups in the benzene ring. The precise amount of the methylolcompounds in the reaction product of these examples has not beenascertained.

We claim as our invention:

1. An N -(1 carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesull'onamide, which is. represented by the followingformula:

in which R. represents the N-monodehydrogenated residue of ap-aminobenze nesulfonamide which is attached to the carbon atom to whichR is linked through the 4-amino nitrogen atom; R represents a member ofthe class of acyl groups consisting of those derived from the alkanoicand haloalkanoic acids of not more than eight carbon atoms, thosederived from the aryl monocarboxylic acids, and those derived from thearyl monosulfonic acidsyand X represents a member of the class ofpositive ions consisting of hydrogen, the alkali metals, the normalequivalents of the alkaline-earth metals, the nitrogen hydrooniurn ionsderived from ammonia, the alkylamines, the alkanolamines, and thepolymethylene diamines.

2. An N -(1 carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesulfonamide in accordance with claim 1, in which Rrepresents the acyl group derived from an alkanoic acid of not more thaneight carbon atoms.

3. An N -(l carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesulfonamide in accordance with claim 1, in which Rrepresents an acetyl group.

4. An N -(l carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesulfonamide in accordance with claim 1, in which Rrepresents of the benzoyl group.

v 5. An N -(1 carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesulfonamide in accordance with claim 1, in which Xrepresents sodium.

6. An N -(1 carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesulfonamide in accordance with claim 1, in which Xrepresents hydrogen.

7. An N -(1 carboxy 1 acylaminoethylthiomethyl) derivative of ap-aminobenzenesulfonamide in accordance with claim 1,.in which Rrepresents an acetyl group and X represents so- 8. A compound which isrepresented by the following formula:

COgNa x Icm-s-cmc -co-om 9. The process of producing a reaction productwhich consists in treating formaldehyde and a p-aminobenzenesulfonamidewith an N-acylcysteine which is represented by the following formula: A

com

uct in accordance with claim 9, in which R of' the N-acylcysteine isderived from an alkanoic acid of not more than eight cart on atoms.

12. The process of producing a reaction product in accordance with claim9, in which R of the N-acylcysteine is derived from an arylmonocarboxylic acid.

13. The process of producing a reaction product in accordance with claim9, in which R2 of the N-acylcysteine is the acetyl radical. v

MORRIS S. mason. OTTO REINMUTH.

